WO2020111018A1 - 免疫チェックポイント阻害薬およびｆｏｌｆｉｒｉｎｏｘ療法との併用によるがん治療 - Google Patents

免疫チェックポイント阻害薬およびｆｏｌｆｉｒｉｎｏｘ療法との併用によるがん治療 Download PDF

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WO2020111018A1
WO2020111018A1 PCT/JP2019/046048 JP2019046048W WO2020111018A1 WO 2020111018 A1 WO2020111018 A1 WO 2020111018A1 JP 2019046048 W JP2019046048 W JP 2019046048W WO 2020111018 A1 WO2020111018 A1 WO 2020111018A1
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cancer
administered
agent according
administration
therapy
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French (fr)
Japanese (ja)
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恵介 木村
将任 黒田
剛幸 岩田
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小野薬品工業株式会社
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Priority to JP2020557713A priority Critical patent/JP7491220B2/ja
Priority to US17/297,339 priority patent/US20220008421A1/en
Priority to EP19891006.9A priority patent/EP3888648A4/en
Priority to KR1020217015103A priority patent/KR20210095868A/ko
Publication of WO2020111018A1 publication Critical patent/WO2020111018A1/ja

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Definitions

  • the present invention relates to a cancer treatment method in combination with an immune checkpoint inhibitor and FOLFIRINOX therapy.
  • FOLFIRINOX therapy (hereinafter sometimes abbreviated as “FFX therapy”) is one of the standard treatments performed for patients with unresectable pancreatic cancer. However, it is known that adverse events such as bone marrow suppression, nausea and vomiting occur frequently, and to alleviate them, the dose of modified FOLFIRINOX therapy (hereinafter, abbreviated as “mFFX therapy”) may be reduced. There is also).
  • immune checkpoint inhibitors such as PD-1 (Programmed Cell Death-1) or its ligand PD-L1 (Programmed Cell Death Ligand-1), so-called immune checkpoint inhibitors (hereinafter, “ It may be abbreviated as "immune CP inhibitor”.) has achieved certain results in clinical practice.
  • the purpose of the present invention is to provide a new treatment method for cancer.
  • the inventors of the present invention as a result of diligent studies, have found that a therapeutic method in which an immune checkpoint inhibitor and FOLFIRINOX therapy or a dose-reducing regimen thereof are combined and combined can be an effective cancer therapeutic method, and completed the present invention.
  • an immune checkpoint inhibitor (hereinafter sometimes abbreviated as “immune CP inhibitor”), which is administered in combination with FFX therapy or a dose-reducing regimen thereof, as an active ingredient. Cancer progression suppression, recurrence suppression and/or therapeutic agent; [2] The above-mentioned [1], wherein the immune CP inhibitor is administered once at about 1 to 10 mg/kg (body weight) or once at about 200 to 1200 mg at an interval of about 2 to 4 weeks.
  • Agent [3] 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg or 10 mg/kg as the immune CP inhibitor (Body weight), the agent according to the above [1] or [2]; [4] 200 mg, 240 mg, 250 mg, 280 mg, 300 mg, 320 mg, 350 mg, 360 mg, 400 mg, 420 mg, 450 mg, 480 mg, 500 mg, 540 mg, 560 mg, 600 mg, 640 mg, 700 mg, 720 mg, 750 mg once as the immune CP inhibitor , 800 mg, 840 mg, 900 mg, 1000 mg, 1080 mg, 1100 mg, 1120 mg or 1200 mg, the agent according to the above item [1] or [2]; [5] The agent according to any one of [1] to [4] above, wherein the immune CP inhibitor is administered at an interval of 2 weeks, 3 weeks or 4 weeks; [6] The agent according to any
  • L-OHP oxaliplatin
  • Levofolinate calcium (hereinafter abbreviated as “l-LV”) 200 mg/m 2 was intravenously administered over 2 hours, and irinotecan hydrochloride hydrate (hereinafter, “CPT -11”.) 180 mg/m 2 was intravenously administered over 1.5 hours, and 5-FU 400 mg/m 2 was rapidly intravenously administered after completion of administration of 1-LV, and further 5 -FU 2400 mg/m 2 was continuously administered intravenously over 46 hours, and the series of administrations (hereinafter, any of the second and subsequent administrations of the “series of administration” was performed as “any administration after the second cycle”).
  • the agent according to any one of the above items [1] to [27], which is performed every two weeks.
  • the dose of CPT-11 in the FFX therapy or the dose of CPT-11 that is reduced according to the degree of side effect occurrence in the patient in any of the second and subsequent administrations of the FFX therapy is The above-mentioned [28], [31], [33] or [, which is about 150 mg/m 2 , about 120 mg/m 2 , about 90 mg/m 2 or any dose between about 180 and about 90 mg/m 2 .
  • the agent described above; [36] A dose of 5-FU that is continuously intravenously administered in the FFX therapy, or a dose that is reduced depending on the degree of side effect occurrence in the patient in any of the second and subsequent cycles of the FFX therapy.
  • the dose of 5-FU administered intravenously is about 1800 mg/m 2 , about 1200 mg/m 2 or any dose between about 2400 and about 1200 mg/m 2 [28] and [32].
  • the FFX therapy dose-reducing regimen is administered in combination with L-OH 200 mg/m 2 after intravenous administration of L-OHP 85 mg/m 2 over 2 hours.
  • m 2 was administered intravenously over 2 hours, and 30 minutes after the start of l-LV administration, 150 mg/m 2 of CPT-11 was intravenously administered over 1.5 hours, and after administration of 1-LV, 5 -FU 2400 mg/m 2 is administered intravenously over 46 hours, and the series of administration is performed at 2-week intervals (the weight-reduction regimen corresponds to “mFFX therapy”), [1].
  • the weight-reduction regimen corresponds to “mFFX therapy”
  • the agent according to any one of the above items [37] to [39]; [41] The dose of L-OHP in the dose-reducing regimen of the FFX therapy according to the preceding paragraph [37], or in any dose after the second cycle of the dose-reducing regimen, the dose is reduced according to the degree of side effect occurrence in the patient.
  • the dose of CPT-11 in the dose-reducing regimen of FFX therapy according to the preceding paragraph [37], or any of the doses following the second cycle of the dose-reducing regimen is reduced according to the degree of side effect in the patient.
  • the dose of CPT-11 is about 120 mg/m 2 , about 90 mg/m 2 or any dose between about 150 and about 90 mg/m 2 [37], [39] or [41].
  • Listed agents; [43] The degree of side effect occurrence in the patient at the dose of 5-FU continuously intravenously administered in the dose reduction regimen of FFX therapy according to the above [37], or in any of the doses after the second cycle of the dose reduction regimen
  • the dose of continuously administered intravenously 5-FU is reduced to about 1800 mg/m 2 , about 1200 mg/m 2 or any dose between about 2400 and about 1200 mg/m 2 .
  • the immune CP inhibitor is first administered, and at least about 30 minutes after the administration of the immune CP inhibitor is completed,
  • any one of the series of administrations from the second cycle onward is temporarily or continuously performed at 3 week intervals or 4 weeks.
  • the cancer is a solid cancer, and the solid cancer is malignant melanoma (for example, malignant melanoma in the skin, oral mucosal epithelium or in the orbit of the eye), non-small cell lung cancer (for example, squamous non-small cell) Lung cancer and non-squamous non-small cell lung cancer), small cell lung cancer, head and neck cancer (eg oral cavity cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer,
  • malignant melanoma for example, malignant melanoma in the skin, oral mucosal epithe
  • Lymphoplasmacytic lymphoma mycosis fungoides, Sezary syndrome, chronic or acute lymphocytic leukemia, peripheral T cell lymphoma, extranodal NK/T cell lymphoma, adult T cell leukemia, B cell lymphoblastic leukemia , T-cell lymphoblastic leukemia and lymphoplasmacytoid lymphoma) and Hodgkin lymphoma (eg classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma)), leukemia (eg acute myeloid leukemia and chronic myelogenous leukemia) ), a central nervous system malignant lymphoma, one or more cancers selected from myelodysplastic syndromes and myeloproliferative syndromes; [51] The agent according to any one of the above [1] to [46], wherein the cancer is pediatric cancer or cancer of unknown primary origin; [52] The agent according to the above item [47], wherein the
  • pancreatic cancer The cancer is a solid cancer, and the solid cancer is pancreatic cancer (hereinafter, "pancreatic cancer” may be referred to as “pancreatic cancer”).
  • pancreatic cancer may be referred to as “pancreatic cancer”
  • pancreatic cancer pancreatic cancer
  • agents [54] The agent according to the above item [53], wherein the pancreatic cancer is pancreatic ductal cancer, insulinoma or intraductal papillary mucinous tumor;
  • the agent according to any one of the above items [1] to [54] which is intended for cancer in which the therapeutic effect of an anticancer drug is insufficient or insufficient.
  • an antimetabolite for example
  • TPS Tumor Proportion Score
  • CPS Positive Score
  • the agent according to any one of [68] The agent according to any one of the above items [1] to [66], which is intended for cancer having a low frequency of TMB (the number of mutations per 10 6 bases is less than 10); [69] The agent according to any one of the above items [1] to [68], which is administered only in combination with FFX therapy or a weight reduction regimen thereof; [70] The agent according to any one of [1] to [68] above, which is not used in combination with radiation therapy; [71] The agent according to any one of the above [1] to [68], which is not prescribed as preoperative therapy; [72] The agent according to any one of the above items [1] to [68], which is used in combination with another anticancer drug; [73] Other anticancer agents include alkylating agents, platinum agents, antimetabolites (eg, antifolate, pyridine metabolism inhibitor, purine metabolism inhibitor), ribonucleotide reductase inhibitors, nucleotide analogs, topoisomerases
  • One or more drugs selected from inhibitors, microtubule polymerization inhibitors, microtubule depolymerization inhibitors, antitumor antibiotics, cytokine preparations, antihormonal drugs, molecular targeting drugs and cancer immunotherapeutic drugs [ 72] The agent described above; [74] A therapeutic agent for suppressing the progression, recurrence, and/or treatment of pancreatic cancer, which comprises Nivolumab as an active ingredient, which is administered only in combination with a dose-reducing regimen of FFX therapy, and is administered once as the Nivolumab.
  • pancreatic cancer is pancreatic cancer having distant metastasis that has not been treated with an anticancer drug.
  • An immune CP inhibitor or an immune CP inhibitor which is administered in combination with FFX therapy or a dose-reducing regimen thereof and is used for cancer progression suppression, recurrence suppression and/or treatment;
  • [3-1] FFX therapy Alternatively, a method for suppressing the progression of cancer, suppressing recurrence, and/or treating the method, which comprises administering a weight-reduction regimen thereof and an immune CP inhibitor or an immune CP inhibitor to a patient.
  • the present invention provides a new treatment method for cancer, which is difficult to treat with existing therapies.
  • the “immunity checkpoint inhibitor” in the present specification refers to, for example, an anti-PD-1 antibody (eg, Nivolumab, Cemiplimab (REGN-2810), Pembrolizumab (MK-3475), Spartalizumab (PDR-001), Tislelizumab (BGB).
  • an anti-PD-1 antibody eg, Nivolumab, Cemiplimab (REGN-2810), Pembrolizumab (MK-3475), Spartalizumab (PDR-001), Tislelizumab (BGB).
  • AMP-514 (MEDI0680), Dostarlimab (ANB011/TSR-042), Tripalimab (JS001), Camrelizumab (SHR-1210), Genolimzumab (CBT-501), Sintilimab (IBI308), STI-A1110, ENUM 388D4 , ENUM 244C8, GLS010, MGA012, AGEN2034, CS1003, HLX10, BAT-1306, AK105, AK103, BI754091, LZM009, CMAB819, Sym021, GB226, SSI-361, JY034, HX008, ISU106, ABBV181, BCD-100, PF -06801591, CX-188, JNJ-63723283 and AB122), anti-PD-L1 antibody (for example, Atezolizumab (RG7446/MPDL3280A), Avelumab (PF-06834635/MSB0010718C
  • Nivolumab can be produced according to the method described in WO2006/121168, Pembrolizumab can be produced according to the method described in WO2008/156712, and BMS-936559 is described in WO2007/005874. Can be produced according to the method described above, and Ipilimumab can be produced according to the method described in WO2001/014424.
  • preferred immune CP inhibitors are anti-PD-1 antibody, anti-PD-L1 antibody and anti-CTLA-4 antibody, and preferred anti-PD-1 antibody is Nivolumab, Cemiplimab, Pembrolizumab, These are Spartalizumab, Tislelizumab, Tripalimab, Sintilimab and Camrelizumab.
  • the anti-PD-L1 antibody is preferably Atezolizumab, Avelumab, Durvalumab and BMS-936559, and the anti-CTLA-4 antibody is preferably Ipilimumab and Tremelimumab.
  • the anti-PD-1 antibody is more preferably Nivolumab, Cemiplimab and Pembrolizumab, and even more preferably Nivolumab.
  • the “FFX therapy” in the present invention refers to cancer caused by a combination of oxaliplatin (L-OHP), irinotecan hydrochloride hydrate (CPT-11), levofolinate calcium (1-LV) and fluorouracil (5-FU).
  • L-OHP oxaliplatin
  • CPT-11 irinotecan hydrochloride hydrate
  • levofolinate calcium (1-LV) a fluorouracil
  • fluorouracil 5-FU
  • the "reduction dose regimen" of the FFX therapy means to reduce the dose of any of the four drugs administered in the FFX therapy from the initial administration or to discontinue the administration itself, or any administration after the first cycle. Depending on the degree of the side effect observed by the above, the dosage is reduced in any administration after the second cycle or the administration of any of the four agents is discontinued.
  • the dose of L-OHP is about 65 mg/m 2 , about 50 mg/m 2 or about 85- It may be any dose between about 50 mg/m 2 and the dose of CPT-11 is about 150 mg/m 2 , about 120 mg/m 2 , about 90 mg/m 2 or about 180 to about 90 mg/m 2.
  • the dose of 5-FU administered continuous intravenous comprises about 1800 mg / m 2, about 1200 mg / m 2 or from about 2400 to about 1200 mg / m 2 It may be any dose in between.
  • the dose reduction regimen in any of the administrations in the second and subsequent cycles in the FFX therapy, even if the rapid intravenous administration of 5-FU is discontinued depending on the degree of side effect occurrence in the patient.
  • the dose of L-OHP is reduced to about 65 mg/m 2 , about 50 mg/m 2 or any dose between about 85 and about 50 mg/m 2 depending on the degree of side effects in the patient, or Administration of L-OHP may be discontinued, and the dose of CPT-11 may be adjusted to about 150 mg/m 2 , about 120 mg/m 2 , about 90 mg/m 2 or about 180 depending on the degree of side effect in the patient.
  • the dose may be reduced to any dose between about 90 mg/m 2 or the administration of CPT-11 may be discontinued, and the dose of 5-FU to be continuously intravenously administered may be adjusted according to the degree of side effect in patients.
  • the dose may be reduced or the administration of the 5-FU may be discontinued at about 1800 mg/m 2 , about 1200 mg/m 2 or any dose between about 2400 and about 1200 mg/m 2 .
  • irinotecan hydrochloride hydrate may be simply abbreviated as “irinotecan”, and similarly, levofolinate calcium may be simply abbreviated as “levofolinate”.
  • L-OHP 85 mg/m 2 is intravenously administered for 2 hours, and then l-LV 200 mg/m 2 is intravenously administered for 2 hours, and l-LV is administered.
  • 30 minutes after the start 150 mg/m 2 of CPT-11 was intravenously administered over 1.5 hours, and after the administration of 1-LV was completed, 400 mg/m 2 of 5-FU was intravenously administered over 46 hours,
  • the series of administrations may be given at 2 week intervals, in particular the weight reduction regimen is recognized as modified FOLFIRINOX therapy (mFFX therapy).
  • the dose of L-OHP is about 65 mg/m 2 , about 50 mg/m 2 or any administration between about 85 and about 50 mg/m 2.
  • the dose of CPT-11 may be about 120 mg/m 2 , about 90 mg/m 2 or any dose between about 150 and about 90 mg/m 2 , continuous intravenous
  • the dose of 5-FU administered internally may be about 1800 mg/m 2 , about 1200 mg/m 2 or any dose between about 2400 and about 1200 mg/m 2 .
  • the dose of L-OHP is about 65 mg/m 2 , about 50 mg/m 2 or about 85-depending on the degree of side effect in the patient.
  • the dose may be reduced to any dose between about 50 mg/m 2 or the administration of L-OHP may be discontinued, and the dose of CPT-11 may be adjusted to about 120 mg/m 2 depending on the degree of side effects in the patient.
  • About 90 mg/m 2 or reduced to any dose between about 150 and about 90 mg/m 2 or CPT-11 may be discontinued and the dose of 5-FU administered continuously intravenously
  • the dose is reduced to about 1800 mg/m 2 , about 1200 mg/m 2 or any dose between about 2400 and about 1200 mg/m 2 or the administration of the 5-FU is discontinued, depending on the degree of side effects of the patient. May be.
  • the series of administrations of the FFX therapy, the mFFX therapy, or a dose-reducing regimen thereof is temporarily or continuously set to 3 weeks or 4 weeks depending on the degree of side effect occurrence in the patient. May be.
  • radiation therapy refers to a therapeutic method of irradiating radiation to kill cancer cells, for example, intensity-modulated radiation therapy (IMRT), image-guided radiation therapy (IGRT), stereotactic radiation therapy. (SRT), stereotactic body radiation therapy (SBRT), stereotactic surgery (SRS), proton beam therapy and heavy ion beam therapy and brachytherapy.
  • IMRT intensity-modulated radiation therapy
  • IGRT image-guided radiation therapy
  • SRT stereotactic radiation therapy
  • SBRT stereotactic body radiation therapy
  • SRS stereotactic surgery
  • preoperative therapy refers to precedent treatment with an anticancer drug or the like, and mainly prevents postoperative micrometastases of invasive cancer and prevents recurrence. It is done for the purpose.
  • the “agent of the present invention” or the “agent of the present invention” includes, in addition to immune CP inhibitors, oxaliplatin, irinotecan hydrochloride hydrate, levofolinate used in FFX therapy, mFFX therapy or their weight-loss regimens. Included are drugs containing the active ingredients calcium and fluorouracil.
  • the “treatment method of the present invention” or “treatment method of the present invention” in the present specification means a combination therapy of an immune CP inhibitor and FFX therapy, mFFX therapy, or a weight reduction regimen thereof for a cancer patient. ..
  • the cancer to which the drug or treatment method of the present invention is applied includes any solid cancer and hematological cancer, and examples of the solid cancer include malignant melanoma (eg, skin, oral mucosal epithelium, or intraorbital etc.).
  • non-small cell lung cancer eg, squamous non-small cell lung cancer and non-squamous non-small cell lung cancer
  • small cell lung cancer head and neck cancer
  • oral cancer nasopharyngeal cancer, oropharynx Cancer, hypopharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, salivary gland cancer and tongue cancer
  • renal cell cancer eg clear cell renal cell carcinoma
  • breast cancer ovarian cancer (eg, Serous ovarian cancer and clear cell adenocarcinoma of the ovary), Uterine cancer (eg cervical cancer and endometrial cancer),
  • Anal cancer eg anal canal cancer
  • Colorectal cancer Rectal cancer , Colon cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, esophagogastric junction cancer, pancreatic cancer (eg pancreatic duct cancer, insulinoma and intraductal papillary mucinous
  • sarcomas include bone and soft tissue sarcomas (eg, Ewing sarcoma, childhood rhabdomyosarcoma, leiomyosarcoma of the uterine body, chondrosarcoma, lung sarcoma, osteosarcoma, congenital fibrosarcoma) and Examples include Kaposi's sarcoma.
  • hematological cancers include multiple myeloma, malignant lymphoma (for example, non-Hodgkin lymphoma (for example, follicular lymphoma, diffuse large B-cell lymphoma, MALT lymphoma, lymphoplasmacellular lymphoma, fungus).
  • malignant lymphoma for example, non-Hodgkin lymphoma (for example, follicular lymphoma, diffuse large B-cell lymphoma, MALT lymphoma, lymphoplasmacellular lymphoma, fungus).
  • Mycosis fungoides Sézary syndrome, chronic or acute lymphocytic leukemia, peripheral T cell lymphoma, extranodal NK/T cell lymphoma, adult T cell leukemia, B cell lymphoblastic leukemia, T cell lymphoblastic leukemia And lymphoid plasma cell lymphoma) and Hodgkin lymphoma (eg classic Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma)) and leukemia (eg acute myeloid leukemia and chronic myelogenous leukemia), central nervous system malignant lymphoma , Myelodysplastic syndrome and myeloproliferative syndrome.
  • Hodgkin lymphoma eg classic Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma
  • leukemia eg acute myeloid leukemia and chronic myelogenous leukemia
  • cancers to which the drug or treatment method of the present invention is applied include childhood cancers and cancers of unknown primary origin.
  • the cancer to which the drug or treatment method of the present invention is applied is preferably pancreatic cancer and biliary tract cancer
  • pancreatic cancer is preferably pancreatic duct cancer, neuroendocrine tumor insulinoma and intraductal papillary mucinous tumor. Is.
  • the term “treatment” for cancer includes, for example, (i) reduction of tumor cell proliferation, (ii) reduction of symptoms caused by cancer, and (iii) quality of life of cancer patients. Improving, (iv) reducing the dose of other anti-cancer drugs or co-therapeutic drugs that have already been administered, and/or (v) a treatment performed to prolong the survival of cancer patients.
  • the term “suppression of progression” of cancer means delaying the progression of cancer, stabilizing the symptoms associated with cancer, and slowing the progression of symptoms.
  • “suppressing recurrence of cancer” means preventing cancer recurrence prophylactically in patients whose cancer lesions have been completely or substantially eliminated or removed by cancer treatment or resection surgery. To do.
  • the drug or treatment method of the present invention is applied to the following cancer patients, that is, (a) a patient who has an insufficient or insufficient therapeutic effect by an anticancer drug, or a patient who has become worse after treatment with an anticancer drug, (b) Patients with curative or unresectable, metastatic, recurrent, refractory and/or distant metastatic cancer (c) TPS of 50% or more, 25% or more, 10% or more, 5% or more or 1% or more Certain cancer patients, (d) cancer patients with CPS of 20% or more, 10% or more, 5% or more or 1% or more, (e) cancer patients with MSI-H and/or dMMR, (F) May be prescribed to patients with cancer in which TMB is common.
  • the drug or therapeutic method of the present invention is applied to the following cancer patients, that is, (g) a patient who has not been treated with an anticancer drug, (h) TPS is less than 50%, less than 25%, Less than 5%, less than 5% or less than 1%, (i) CPS less than 20%, less than 10%, less than 5% or less than 1%, (j) MSI-H And/or prescription may be more desirable for patients with cancers who do not have dMMR or have MSI-L, or (k)TMB having a low frequency.
  • cancer patients for whom the drug or therapeutic method of the present invention is required include cancer patients who have not been previously treated with an anticancer drug and/or have distant metastases, particularly pancreatic cancer patients.
  • an anticancer drug for example, an alkylating drug, a platinum preparation, an antimetabolite (for example, a folate antimetabolite, a pyridine metabolism inhibitor, a purine metabolism inhibitor), a ribonucleotide reductase inhibitor, a nucleotide Analogues, topoisomerase inhibitors, microtubule polymerization inhibitors, microtubule depolymerization inhibitors, antitumor antibiotics, cytokine preparations, antihormonal drugs, molecular targeting drugs and cancer immunotherapeutic drugs and drugs classified into each Can be mentioned.
  • an antimetabolite for example, a folate antimetabolite, a pyridine metabolism inhibitor, a purine metabolism inhibitor
  • a ribonucleotide reductase inhibitor for example, a folate antimetabolite, a pyridine metabolism inhibitor, a purine metabolism inhibitor
  • a ribonucleotide reductase inhibitor for example, a folate antimetabol
  • the immune CP inhibitor of the present invention can be administered in the following dosage regimens in combination with FFX therapy, mFFX therapy, or a combination thereof with a dose-reducing regimen.
  • an immune CP inhibitor for example, about 1 to 10 mg/kg (body weight) once or about 200 to 1200 mg once as an active ingredient of an immune CP inhibitor is given at 2 to 4 week intervals for about 30 minutes to about 60 minutes or about 60 minutes or more. It can be administered intravenously (eg, intravenous drip).
  • the dose in body weight conversion per administration for example, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg /Kg or 10 mg/kg
  • the dose per administration is, for example, 200 mg, 240 mg, 250 mg, 280 mg, 300 mg, 320 mg, 350 mg, 360 mg, 400 mg, 420 mg, 450 mg, 480 mg, 500 mg, 540 mg, 560 mg, 600 mg, 640 mg, 700 mg, 720 mg, 750 mg, 800 mg, 840 mg, 900 mg, 1000 mg, 1080 mg, 1100 mg, 1120 mg or 1200 mg.
  • the administration interval is, for example, 2 weeks, 3 weeks or 4 weeks, and the administration time for one administration is, for example, about 30 minutes, about 60 minutes or about 60 minutes or more.
  • Nivolumab which is an anti-PD-1 antibody
  • it is administered at the following dosage and administration. That is, for patients with malignant melanoma, 3 mg/kg (body weight) as Nivolumab was administered once every 2 weeks or 2 mg/kg (body weight) once every 3 weeks as an intravenous infusion, and non-small cell lung cancer and renal cells were administered.
  • Each patient with cancer, classic Hodgkin's lymphoma, head and neck cancer, gastric cancer and malignant pleural mesothelioma is given 3 mg/kg (body weight) of Nivolumab once every two weeks as an intravenous infusion.
  • Nivolumab As another usage/dose, for example, malignant melanoma, non-small cell lung cancer, renal cell carcinoma, urothelial cancer, MSI-H or dMMR-positive colon cancer (including pediatric patients aged 12 years or older), To patients with gastric cancer, hepatocellular carcinoma, small cell lung cancer, and malignant pleural mesothelioma, 240 mg of Nivolumab is administered once every two weeks or 480 mg once every four weeks. In addition, as another dosage and administration, for example, in patients with malignant melanoma, in combination with Ipilimumab, 1 mg/kg (body weight) of Nivolumab is intravenously infused four times at 3-week intervals, and then Nivolumab is administered.
  • Nivolumab, 240 mg once every 2 weeks May be given as an intravenous drip in.
  • 240 mg once as Nivolumab was infused intravenously four times at intervals of 3 weeks, and then 240 mg once as Nivolumab was infused intravenously at intervals of two weeks. It may be done.
  • Pembrolizumab which is the same anti-PD-1 antibody, it is administered in the following dosage regimen.
  • malignant melanoma non-small cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, MSI-H or dMMR positive solid cancer or colon cancer, urothelial cancer, cervical cancer, primary mediastinal B cell lymphoma, liver
  • MSI-H or dMMR positive solid cancer or colon cancer urothelial cancer
  • cervical cancer primary mediastinal B cell lymphoma
  • liver Each patient with cell carcinoma, gastric cancer and Merkel cell carcinoma receives 200 mg of pembrolizumab once every 3 weeks.
  • Pembrolizumab is 1 Intravenous drip infusion of 2 mg/kg (body weight) (up to 200 mg once) is given every 3 weeks.
  • Avelumab which is an anti-PD-L1 antibody
  • each patient with Merkel cell carcinoma and urothelial carcinoma receives 10 mg/kg (body weight) of Avelumab once every two weeks. It is administered by injection.
  • Atezolizumab which is the same PD-L1 antibody, is administered at 1200 mg as Atezolizumab once every 3 weeks to patients with non-small cell lung cancer and urothelial cancer, and paclitaxel for patients with triple negative breast cancer.
  • the dose of Atezolizumab will be 840 mg once every 2 weeks.
  • Durvalumab which is the same PD-L1 antibody, is administered to each patient with non-small cell lung cancer and urothelial cancer as an intravenous infusion of 10 mg/kg (body weight) once every 2 weeks as Durvalumab.
  • Ipilimumab which is an anti-CTLA-4 antibody
  • 3 mg/kg (body weight) once daily as Ipilimumab was administered to malignant melanoma patients alone or in combination with Nivolumab four times at three-week intervals.
  • Nivolumab 1 mg/kg (body weight) once daily as Ipilimumab, administered four times at 3-week intervals.
  • Intravenous drip infusion is the preferred administration form for intravenous administration of these immune CP inhibitors.
  • L-OHP 85 mg/m 2 was intravenously administered over 2 hours and then 1-LV 200 mg/m 2 was intravenously administered over 2 hours in combination with the above-exemplified immune CP inhibitors.
  • 30 minutes after the start of administration of l-LV 180 mg/m 2 of CPT-11 was intravenously administered over 1.5 hours, and after the administration of 1-LV, 400 mg/m 2 of 5-FU was administered.
  • Intravenous intravenous administration may be followed by continuous intravenous administration of 5-FU 2400 mg/m 2 over 46 hours, and the series of administrations may be prescribed at 2-week intervals.
  • the dose of 5-FU that is L-OHP, CPT-11, and/or continuous intravenous administration is set as described above without performing rapid intravenous administration of 5-FU from the initial administration.
  • 5-FU rapid intravenous administration may be stopped depending on the degree of side effect in the patient, and the degree of side effect in the patient may be reduced.
  • the dose of L-OHP, CPT-11 and/or continuous intravenously administered 5-FU may be reduced as described above, or each administration itself may be discontinued.
  • L-OHP 85 mg/m 2 was intravenously administered over 2 hours and then 1-LV 200 mg/m 2 was intravenously administered over 2 hours in combination with the above-mentioned immune CP inhibitors.
  • CPT-11 150 mg/m 2 was intravenously administered over 1.5 hours
  • 5-FU 2400 mg/m 2 was further administered after 1-LV administration for 46 hours.
  • the series of administrations may be performed at 2-week intervals.
  • the dose of L-OHP, CPT-11 and/or 5-FU continuously intravenously administered from the first administration may be set as described above, and any of the second and subsequent cycles may be set.
  • the dose of L-OHP, CPT-11 and/or 5-FU continuously intravenously administered is reduced as described above, or The administration itself may be discontinued.
  • the series of administrations of the FFX therapy, the mFFX therapy, or their weight-reducing regimens may be set to three-week intervals or four-week intervals temporarily or continuously depending on the degree of side effect occurrence in the patient. Good.
  • Nivolumab is administered at 3 mg/kg (body weight) or 240 mg once every 2 weeks, or 480 mg once every 4 weeks.
  • Intravenous administration eg, intravenous infusion
  • L-OHP 85 mg/m 2 was administered intravenously over 2 hours, followed by l-LV 200 mg/m 2.
  • CPT-11 150 mg/m 2 was intravenously administered over 1.5 hours, and after completion of 1-LV administration, 5- FU 2400 mg/m 2 can be administered intravenously over 46 hours with the series of administrations occurring at 2 week intervals.
  • a method of intravenous administration for example, intravenous drip
  • 480 mg once as Nivolumab at intervals of 4 weeks for 30 minutes is preferable.
  • the immune CP inhibitor is administered first, and at least after the administration of the immune CP inhibitor is completed. It is preferred to start FFX therapy, mFFX therapy or their weight loss regimen after about 30 minutes.
  • the treatment method of the present invention is started by administering the immune CP inhibitor and FFX therapy, mFFX therapy, or their weight reduction regimens first on the same day in the combination.
  • the drug or therapeutic method of the present invention comprises (1) suppressing the progression of cancer and/or enhancing the therapeutic effect, (2) reducing the dose of another drug used in combination, and/or (3).
  • the dosage form in the case of prescribing in combination with other drug may be in the form of a combination drug in which the other drug is compounded in any one preparation of the drug of the present invention, or a separate preparation.
  • the administration form may be as follows.
  • the dose of the other drug can be appropriately selected based on the dose clinically used.
  • other drugs may be administered in combination of any two or more kinds at an appropriate ratio.
  • the above-mentioned other drugs include not only those which have been found up to now but those which will be found in the future.
  • the "other anticancer drug” that is mentioned as a main example of the other drug is an oxaliplatin, an irinotecan hydrochloride hydrate, an anticancer drug excluding levofolinate calcium and fluorouracil, for example, an alkylating drug (for example, , dacarbazine, Nimustine, Temozolomide, Fotemustine, bendamustine, Cyclophosphamide, Ifosfamide, Carmustine, Chlorambucil and Procarbazine), platinum preparations (eg Cisplatin, Carboplatin, Nedaplatin and Oxaliplatin), antimetabolites (eg antifolate) (eg antifolate) , Pemetrexed, Leucovorin and Methotrexate), pyridine metabolism inhibitors (eg TS-1®, 5-fluorouracil, UFT, Carmofur, Doxifuridine, FdUrd, Cytarabine and Capecitabine), purine
  • examples of the molecular targeting drug that can be mentioned as another anticancer drug include, for example, ALK inhibitors (for example, Crizotinib, Ceritinib, Ensartinib, Alectinib and Lorlatinib), BCR-ABL inhibitors (for example, Imatinib and Dasatinib), EGFR inhibitors (eg Erlotinib, EGF816, Afatinib, Osimertinib mesilate, Gefitinib and Rociletinib), B-Raf inhibitors (eg Sorafenib, Vemurafenib, TAK-580, Dabrafenib, Encorafenib, LXH254, Emurafenib and BGB-3111), VEGF.
  • ALK inhibitors for example, Crizotinib, Ceritinib, Ensartinib, Alectinib and Lorlatinib
  • BCR-ABL inhibitors for example,
  • Inhibitors eg Bevacizumab, Apatinib, Lenvatinib, Aflibercept and Axitinib
  • FGFR inhibitors eg AZD4547, B-701, FGF401 and INCB054828
  • c-Met inhibitors eg Savolitinib, merestinib, Capmatinib, INC280 and Glesatinib.
  • Axl inhibitors eg ONO-7475 and BGB324
  • Mek inhibitors eg Cobimetinib, Binimetinib, Selumetinib and Trametinib
  • CDK inhibitors eg Dinaciclib, Abemaciclib, Palbociclib and trilaciclib
  • Btk inhibitors eg.
  • TGFbR1 inhibitor eg Galunisertib
  • Cancer cell stemness kinase inhibitor eg Amcasertib
  • FAK inhibitor eg Defactinib
  • Syk/FLT3 dual inhibitor eg TAK-659
  • ATR inhibitors eg AZD6738
  • Wee1 kinase inhibitors eg AZD1775
  • multi-tyrosine kinase inhibitors eg , Sunitinib, Pazopanib, Cabozantinib, Regorafenib, Nintedanib, Sitravatinib and Midostaurin
  • anti-CD30 Antibodies eg Brentuximab Vedotin
  • anti-CD38 antibodies eg Daratumumab
  • anti-DR5 antibodies eg DS-8273a
  • anti-CA125 antibodies eg Oregovomab
  • anti-DLL4 antibodies eg Demcizumab
  • anti-fucosyl GM1 antibody For example, BMS-986012
  • anti-gpNMB antibody for example, Glembatumumab vedotin
  • anti-Mesothelin antibody for example, BMS-986148
  • anti-MMP9 antibody for example, Andecaliximab
  • anti-GD2 antibody for example, Dinutuximab- ⁇
  • anti- c-Met antibody eg ABT-399
  • anti-FOLR1 antibody eg Mirvetuximab soravtansine
  • anti-Ang2-VEGF bispecific antibody eg Mirvetuximab soravtansine
  • a cancer immunotherapeutic agent which is mentioned as another anticancer agent is a cancer immunotherapeutic agent having a mechanism of action different from that of any of the immune CP inhibitors of the present invention, and for example, anti-PD-1 Antibodies (eg Nivolumab, Cemiplimab (REGN-2810), Pembrolizumab (MK-3475), Spartalizumab (PDR-001), Tislelizumab (BGB-A317), AMP-514 (MEDI0680), Dostarlimab (ANB011/TSR-042), Toripalimab (JS001), Camrelizumab (SHR-1210), Genolimzumab (CBT-501), Sintilimab (IBI308), STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012, AGEN2034, CS1003, BAT-1306, AK105, AK103, BI 754091, LZM009, CM
  • Atezolizumab (RG7446/MPDL3280A), Avelumab (PF-06834635/MSB0010718C), Durvalumab (MEDI4736), BMS-936559, STI-1014, KN035, LY3300054, SHR-1316, CS1001 (WBP3155), MSB2311, BGB-A333, KL.
  • PD-1 antagonists eg AUNP-12, BMS-M1 to BMS-M10
  • PD-L1/VISTA antagonists eg CA-170 etc.
  • PD-L1/TIM3 antagonists eg , CA-327
  • anti-CTLA-4 antibody eg Ipilimumab (MDX-010)
  • Antibodies eg, Enoblituzumab
  • anti-ICOS agonist antibodies eg, JTX-2011 and GSK3359609
  • anti-CD4 antibodies eg, MTR
  • MTR anti-CD4 antibodies
  • anti-DEC-205 antibody/NY-ESO-1 fusion protein eg, CDX-1401
  • anti-SLAMF7 antibody eg, Elotuzumab
  • anti-CD73 antibody eg, Oleclumab and BMS-986179
  • Anti-CD122 antibody such as NKTR-214
  • antibody drugs include, for example, anti-IL-1 ⁇ antibody (eg, Canakinumab) and anti-CCR2 antibody (eg, Plozalizumab).
  • Antiemetics that may be mentioned as major examples of other drugs include, for example, corticosteroids (eg Dexamethasone and methylprednisolone), 5-HT 3 receptor antagonists (eg Azasetron, Indisetron, Ondansetron, Granisetron, Ramosetron and Palanosetron). ), NK1 receptor antagonists (eg Aprepitant and Fosaprepitant), dopamine D 2 receptor antagonists (eg Domperidone and Metoclopramide), benzodiazepine anxiolytics (eg Alprazolam and Lorazepam), phenothiazine antipsychotics (eg.
  • corticosteroids eg Dexamethasone and methylprednisolone
  • 5-HT 3 receptor antagonists eg Azasetron, Indisetron, Ondansetron, Granisetron, Ramosetron and Palanosetron
  • NK1 receptor antagonists eg Aprepitant and
  • the injection or the infusion may be in the form of an aqueous solution, a suspension or an emulsion.
  • a pharmaceutically acceptable carrier for example, distilled water for injection, physiological saline, glucose solution and isotonic solution (for example, sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, A solution of borax, propylene glycol, etc.) can be used.
  • a solvent used for injection or infusion for infusion for example, distilled water for injection, physiological saline, glucose solution and isotonic solution (for example, sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, A solution of borax, propylene glycol, etc.) can be used.
  • examples of the pharmaceutically acceptable carrier include stabilizers, solubilizers, suspending agents, emulsifiers, soothing agents, buffers, preservatives, preservatives, pH adjusters and antioxidants.
  • examples of the stabilizer include various amino acids, albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol, propylene glycol, polyethylene glycol, ascorbic acid, sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, Dibutylhydroxytoluene or the like can be used.
  • solubilizing agent examples include alcohols (eg, ethanol), polyalcohols (eg, propylene glycol, polyethylene glycol, etc.), nonionic surfactants (eg, Polysorbate 20 (registered trademark), Polysorbate 80 (registered trademark). ), HCO-50, etc.) can be used.
  • alcohols eg, ethanol
  • polyalcohols eg, propylene glycol, polyethylene glycol, etc.
  • nonionic surfactants eg, Polysorbate 20 (registered trademark), Polysorbate 80 (registered trademark).
  • HCO-50 etc.
  • the suspending agent for example, glyceryl monostearate, aluminum monostearate, methyl cellulose, carboxymethyl cellulose, hydroxymethyl cellulose, sodium lauryl sulfate and the like can be used.
  • emulsifier for example, gum arabic, sodium alginate, tragacanth and the like can be used.
  • the soothing agent for example, benzyl alcohol, chlorobutanol, sorbitol and the like can be used.
  • the buffer for example, phosphate buffer, acetate buffer, borate buffer, carbonate buffer, citrate buffer, Tris buffer, glutamate buffer, epsilon aminocaproate buffer, etc. can be used.
  • the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate, chlorobutanol, benzyl alcohol, benzalkonium chloride, sodium dehydroacetate, sodium edetate, boric acid and borohydride. Sand or the like can be used.
  • preservative for example, benzalkonium chloride, paraoxybenzoic acid, chlorobutanol and the like can be used.
  • pH adjuster for example, hydrochloric acid, sodium hydroxide, phosphoric acid, acetic acid or the like can be used.
  • antioxidants examples include (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite and sodium sulfite, (2) ascorbyl palmitate, butylated hydroxyanisole, Use oil-soluble antioxidants such as butylated hydroxytoluene, lecithin, propyl gallate, ⁇ -tocopherol and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid, sorbitol, tartaric acid, phosphoric acid, etc. You can be water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite and sodium sulfite, (2) ascorbyl palmitate, butylated hydroxyanisole, Use oil-soluble antioxidants such as butylated hydroxytoluene, lecithin, propyl gallate, ⁇ -tocopherol and (3) metal chelating agents such as citric acid,
  • an additive in the formulation for example, D-mannitol, sodium citrate hydrate, sodium chloride, diethylenetriaminepentaacetic acid, polysorbate 80 and a pH regulator Is mentioned.
  • examples of additives in the formulation include L-histidine, L-histidine hydrochloride hydrate, purified sucrose and polysorbate 80.
  • the additives in the formulation include, for example, D-mannitol, polysorbate 20, glacial acetic acid and sodium hydroxide.
  • examples of additives in the formulation include L-histidine, glacial acetic acid, purified sucrose and polysorbate 20.
  • the immune CP inhibitor whose active ingredient is Durvalumab examples of additives in the preparation include L-histidine, L-histidine hydrochloride hydrate, trehalose hydrate and polysorbate 80.
  • examples of additives in the preparation include, for example, trometamol hydrochloride, sodium chloride, D-mannitol, diethylenetriaminepentaacetic acid, polysorbate 80 and other pH adjusters.
  • the injectable solution or infusion solution for infusion can be produced by sterilizing it in the final step, or by sterilizing by an aseptic operation method, for example, filtering with a filter or the like, and then filling an aseptic container.
  • an aseptic operation method for example, filtering with a filter or the like, and then filling an aseptic container.
  • a sterile powder obtained by vacuum drying and freeze-drying (which may contain a powder of a pharmaceutically acceptable carrier) is dissolved in an appropriate solvent before use. You can also
  • Example 1 A multi-center, open-label study to evaluate the efficacy and safety of Nivolumab in combination with mFFX therapy in patients with pancreatic cancer.
  • the purpose of this study is to examine the efficacy and safety of Nivolumab in combination with mFFX therapy for cancer patients.
  • the clinical trial can evaluate the combined effect of Nivolumab and mFFX therapy.
  • [Target patient] Pancreatic cancer patients with distant metastases who have no history of chemotherapy
  • patient selection criteria At enrollment, patients will be selected for Nivolumab and FFX or mFFX therapy that meet all of the pre-determined patient selection criteria determined in light of the patient selection criteria in each of the trials conducted to date.
  • Nivolumab 480 mg was intravenously administered at 4-week intervals over 30 minutes, and Nivolumab was continuously administered until the prescribed administration discontinuation standard for Nivolumab was met. No change in dose of Nivolumab is allowed.
  • Nivolumab and mFFX therapy were administered on the same day, Nivolumab was administered first, and at least 30 minutes after the end of Nivolumab administration, administration of mFFX therapy was started.
  • Oxaliplatin 85 mg/m 2 was intravenously administered over 2 hours, and then levofolinate 200 mg/m 2 was intravenously administered over 2 hours.
  • Irinotecan 150 mg/m 2 was intravenously administered for 30 hours 30 minutes after the start of administration of levofolinate. Further, after the administration of levofolinate was completed, fluorouracil 2400 mg/m 2 was intravenously administered over 46 hours. This was set as one cycle and repeated every two weeks.
  • the therapeutic agents used in the mFFX therapy of this clinical study were commercial products.
  • the study consists of a screening phase, a treatment phase and a follow-up phase.
  • Figure 1 shows the outline of the clinical trial schedule.
  • enrolled subjects will be started the combined administration according to the above-mentioned “dose and administration period” for Nivolumab and the above-mentioned “dose and administration period” for mFFX therapy, and the following administration for Nivolumab will be performed. Administration was continued according to the criteria and the following dosing criteria for the mFFX method, the dose reduction criteria and the dose at the time of dose reduction.
  • Nivolumab only when it is safely determined that the administration of Nivolumab can be continued. In this case, after confirming the patient's intention to continue treatment before continuing the administration of Nivolumab, record it in the medical record and contact the sponsor (only when it is judged that Nivolumab administration is necessary immediately).
  • the test subject also met all of the predetermined administration criteria determined in consideration of the administration criteria in each clinical trial conducted so far regarding FFX therapy or mFFX therapy. There must be. Administration is postponed until clinical laboratory values on the scheduled administration date return to a condition that meets the criteria, and it is confirmed that the drug is not contraindicated before administration. ⁇ Reduction criteria for mFFX therapy and dose at the time of reduction> Dec. 20, 2013, Notification of Drug and Food Examination 1220 No.
  • the treatment method of the present invention is particularly useful as a new treatment method for cancer that has been difficult to treat with existing therapies.

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US20210395366A1 (en) * 2020-06-18 2021-12-23 Genentech, Inc. Treatment with anti-tigit antibodies and pd-1 axis binding antagonists
WO2022102731A1 (ja) * 2020-11-13 2022-05-19 小野薬品工業株式会社 Ｅｐ４拮抗薬と免疫チェックポイント阻害物質との併用によるがん治療
WO2022260132A1 (ja) * 2021-06-10 2022-12-15 小野薬品工業株式会社 Ｃｄ４７阻害物質、免疫チェックポイント阻害物質および標準療法の併用によるがん治療法
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JP7556468B2 (ja) 2021-06-10 2024-09-26 小野薬品工業株式会社 Ｃｄ４７阻害物質、免疫チェックポイント阻害物質および標準療法の併用によるがん治療法
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EP4376809A4 (en) * 2021-07-29 2025-06-04 Topalliance Biosciences Inc. PHARMACEUTICAL COMPOSITION OF ANTI-PD-1 ANTIBODY AND ITS USE
WO2023070000A1 (en) * 2021-10-20 2023-04-27 William Marsh Rice University Methods of use and administration of encapsulated cells

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JP7491220B2 (ja) 2024-05-28
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TWI818120B (zh) 2023-10-11
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